Response to Pan et al’s “Non-melanoma skin cancer in patients with hereditary hemochromatosis: A case-control study”
Authors: Rory Barry, Gregg Murray, Karl Hazel, John Ryan, Richard E. Watchorn
Journal: Journal of the American Academy of Dermatology (2023)

We read, with interest, the recent article by Pan et al.1Pan C.X. Yang K. Lau C.B. Zhou G. Nambudiri V.E. Nonmelanoma skin cancer in patients with hereditary hemochromatosis: a case-control study.J Am Acad Dermatol. 2023; 88: 692-694https://doi.org/10.1016/j.jaad.2022.07.029Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar This case-control study noted an association between hereditary hemochromatosis (HH) and non-melanoma skin cancers (NMSCs) in an American population, particularly basal cell carcinomas (BCCs). A possible pathomechanism may be due to oxidative stress representing a key component in the pathogenesis of both HH and BCC. Ireland has the highest prevalence of HH in the world, with approximately 1 in 83 people predisposed.2Ryan E. O'Keane C. Crowe J. Hemochromatosis in Ireland and HFE. Blood Cells.Mol Dis. 1998; 24: 428-432https://doi.org/10.1006/bcmd.1998.0211Crossref Scopus (105) Google Scholar As such, we sought to determine if a similar association could be observed in an Irish population. We retrospectively reviewed the histology records of all patients in the hemochromatosis venesection department database in a single, tertiary referral center over 25 years (October 1997-2022). HH carriers and those under 18 years of age were excluded. As a comparison, we used the most recently published (1996-2020) national average annual NMSC cases recorded by the National Cancer Registry of Ireland to the respective average annual Irish population. Fisher's exact test and univariable regression analysis was performed using R. P values were 2-tailed, with P ≤.05 signifying statistical significance. The local hospital ethics committee granted study approval. Of 1480 patients in the database, 1475 met inclusion criteria following initial review. The 5 excluded had insufficient data available to search the hospital's histology records. Only 52 patients (3.5%) had a histologically diagnosed NMSC over this 25-year period, with a total of 115 NMSCs (Table I). No statistically significant association was seen between the average annual number of NMSCs in patients with HH compared with the average general population over a 25-year period (odds ratio, 1.88; 95% CI, 0.78-4.5; P = .16). In subgroup analysis, no statistically significant association was seen in the average annual number of BCCs in patients with HH compared with the average general population over a 25-year period (odds ratio, 1.90; 95% CI, 0.7-5.08; P = .19; Table II).Table IHereditary hemochromatosis patient demographicsPatient characteristicsTotal (n = 1475)Sex, n (%) Male949 (64%) Female526 (36%)Mean current age60 (19-100)Tumor characteristicsn = 115Total patients with NMSC diagnosis, n (%)52 (3.5%)Tumors per patient, mean (SD)2.2 (3.3)BCC43 (2.9%)SCC11 (0.8%)Sex, n (%) Male27 (52%) Female25 (48%)Mean age at first NMSC diagnosis67Total BCC, n (%)94 (82%)BCC per patient with NMSC, mean (SD)2.2 (3.29)Subtype Nodular48 Superficial19 Infiltrative5 Micronodular3 Basosquamous1 Unclassified18Total SCC, n (%)21 (18%)HH genetic mutation, n (%) C282Y homozygous29 (56%) H63D homozygous5 (10%) C282Y/H63D compound heterozygous11 (21%) Data not recorded7 (13%) Mean ferritin at HH diagnosis575 (0-8413)BCC, basal cell carcinoma; HH, hereditary hemochromatosis; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma. Open table in a new tab Table IIUnivariable regression of HH and general population, mean over 25 yearsHHGeneral populationUnadjusted OR/mean differenceP valueNMSC diagnosis4.68009OR, 1.88 (95% CI, 0.78, 4.5).16BCC diagnosis3.766331OR, 1.90 (95% CI, 0.70, 5.08).19BCC, basal cell carcinoma; HH, hereditary hemochromatosis; NMSC, nonmelanoma skin cancer; OR, odds ratio. Open table in a new tab BCC, basal cell carcinoma; HH, hereditary hemochromatosis; NMSC, nonmelanoma skin cancer; SCC, squamous cell carcinoma. BCC, basal cell carcinoma; HH, hereditary hemochromatosis; NMSC, nonmelanoma skin cancer; OR, odds ratio. The National Cancer Registry of Ireland reported an average age-standardized rate of 312 cases per 100,000 population of NMSCs annually between 2018 and 2020, an increase from 156 cases per 100,000 between 1994 and 2011.3Cancer in Ireland 1994-2020: annual statistical report of the National Cancer Registry. National Cancer Registry Ireland.https://www.ncri.ie/sites/ncri/files/pubs/NCRI_AnnualStatisticalReport_2022.pdfDate accessed: January 7, 2023Google Scholar,4Cancer in Ireland 1994-2011: annual statistical report of the National Cancer Registry.https://www.ncri.ie/sites/ncri/files/pubs/annual%20report%202014.pdfDate accessed: January 7, 2023Google Scholar Over the course of our study period (1997-2022), the incidence rate of NMSCs in the HH group was 306 cases per 100,000 population. Our study had limitations. This was a single center, retrospective chart review analyzing only histologically confirmed NMSCs. It can be acknowledged that a small proportion of NMSCs may be diagnosed clinically, specifically superficial BCCs without histologic confirmation. Only histology available in our institution was recorded, and it is possible that NMSCs were excised in other institutions, potentially leading to an underrepresentation of NMSC incidence. Irish dermatologists follow British Association of Dermatology guidelines, whereby BCCs warrant a biopsy for diagnostic clinical doubt, high-risk sites, or histologic subtypes requiring surgical excision.5Nasr I. McGrath E.J. Harwood C.A. et al.British Association of Dermatologists guidelines for the management of adults with basal cell carcinoma 2021.Br J Dermatol. 2021; 185: 899-920https://doi.org/10.1111/bjd.20524Crossref PubMed Scopus (57) Google Scholar The proportion of patients diagnosed with NMSC in this cohort was relatively low, contrasting with the findings reported by Pan et al.1Pan C.X. Yang K. Lau C.B. Zhou G. Nambudiri V.E. Nonmelanoma skin cancer in patients with hereditary hemochromatosis: a case-control study.J Am Acad Dermatol. 2023; 88: 692-694https://doi.org/10.1016/j.jaad.2022.07.029Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Our study suggests that HH is unlikely to represent an independent risk factor. Large case-control studies in an Irish population would be beneficial to further evaluate this suspected risk factor for NMSCs. None disclosed. Response to the article by Barry et al entitled "Nonmelanoma skin cancer in patients with hereditary hemochromatosis: a case-control study"Journal of the American Academy of DermatologyVol. 89Issue 4PreviewTo the Editor: We thank Barry et al1 for their thoughtful retrospective cohort study on the risk association between hereditary hemochromatosis (HH) and nonmelanoma skin cancer (NMSC). The authors conducted a single-institution, retrospective cohort analysis of an Irish population, within which HH was unlikely an independent risk factor for NMSCs.1 We appreciate the authors' attention to this important question. Full-Text PDF